The goal of the proposed investigation is to elucidate the biochemistry of Hurler's syndrome. Hurler's syndrome is here used in its general connotation to refer to genetic chondrodystrophies, many of which have associated neurological deficits. A primary research model is cultured fibroblasts derived from patients with different types of mucopolysaccharidoses. Each type (mutant) is deficient in one of the enzymes in the degradative pathway of mucopoly-saccharides. Establishing the nature of the deficient enzymes, characterizing the linkage groups they hydrolyze, and the biochemical consequences of the deficiencies is a central objective. It is axiomatic that an understanding of mutant biochemistry is facilitated by knowledge of normal biochemistry. Therefore, elucidation of the nature of the enzymes and the linkage groups they hydrolyze in normal mucopolysaccharide catabolism is also a goal of the project. Radioactively labeled compounds derived from or structurally related to mucopolysaccharides will be biosynthesized, isolated and protocols for monitoring their hydrolysis will be developed. Extracts of fibroblasts derived from control subjects will generally serve as the enzyme source to establish normal baseline parameters. Similar preparations from patients with mucopolysaccharidoses will then be examined for deficiencies in catabolism of test substrates. When defects are noted, the reaction will be studied in depth. Physiological substrates generally provide greater specificity and sensitivity than synthetic substrates, so development of diagnostic protocols will constitute one application of effective radioactive substrates. These studies should lead to a better understanding of the biochemical pathology of the mucopolysaccharidoses, provide an input to our knowledge of normal catabolism of mucopolysaccharides, improve diagnostic procedures, and establish a basis for rational approaches to therapy. BIBLIOGRAPHIC REFERENCES: Fujimoto, A., Fluharty, A.L., Kihara, H., Stevens, R.L., and Wilson, M.G. Two alpha-Glucosidases in Cultured Amniotic Fluid Cells. Clin. Res., 23: 145a, 1975. Stevens, R.L., Fluharty, A.L., Fung, D., Peak, S., and Kihara, H. UDP-N-Acetylgalactosamine-4-sulfate Sulfohydrolase Activity of Human Arylsulfatase B. Fed. Proc., 34: 635, 1975.